Background: Preinfarction angina has been recognized as a surrogate for preconditioning episodes. This study was designed to evaluate the cardiovascular effects of preinfarction anginal episodes among acute myocardial infarction (AMI) patients undergoing primary percutaneous coronary intervention (PCI). Materials and Methods: Of 520 patients who had undergone primary PCI, 393 patients were finally included in a prospective cohort study. Standard primary PCI procedure according to the latest guidelines was performed. The patients were divided into three groups based on previous symptoms as follows: asymptomatic (Group A), chronic stable angina (Group B) and unstable angina (Group C). Results: A total of 393 patients were evaluated. 185 (47.1%) patients were described as asymptomatic, 48 (12.2%) had stable angina and 160 (40.7%) were categorized as unstable angina. There was no significant difference among the study groups regarding pre- and post-PCI thrombolysis in myocardial infarction flow grade (P = 0.81). Median of peak post-PCI creatine-kinase-muscle/brain level of Group A (asymptomatic) was 250.5 (115.5–389), and it was significantly higher than Group C (176 [60.00–313.50]) (P = 0.03). Q wave formation was observed in 142 (88.75%), 31 (64.5%), and 96 (52.0%) patients of Group A, B, and C patients, respectively, which was significantly higher in asymptomatic patients (P = 0.002). There was no significant difference among the three groups regarding in-hospital and 6-month mortality (P = 0.36, 0.06, respectively). The composite endpoint of 6-month mortality, acute coronary events, cerebrovascular accidents, and target vessel revascularization was not significantly different between the three groups (P = 0.11). Conclusion: Preinfarction angina among AMI patients undergoing primary PCI seems to have a limited beneficial effect on infarct size, and this benefit was not translated to any clinical benefit.

Ischemic preconditioning is known as the phenomenon in which brief episodes of ischemia can protect the myocardium against a subsequent coronary occlusion. Cellular mechanisms activated in this process delay the irreversible myocardial injury and decrease the extent of necrosis if its followed by reperfusion.[1]

Ischemic preconditioning is divided into acute and delayed (chronic) types. The process consists of different phases. Initially, trigger agents start the transformation process. Some of the identified triggers include adenosine, bradykinin, norepinephrine, opioids, and reactive oxygen species. Memory step is the next phase that keeps the myocardium in a preconditioned state. Finally, there are the end effectors that result in protection from injury. One of the most studied end effectors is mito-adenosine triphosphate (ATP) channels. Protein kinase C, protein tyrosine kinase, and Mitogen activated protein kinases are some other mediators known to be operational in pathways related to this phenomenon.[1],[2]

The potential benefits of preconditioning phenomenon have provoked efforts for its clinical application. It has been revealed that intermittent ischemic episodes induced in remote regions, such as inflation of a pressure cuff in patients arm, can also activate the process and potentially produce the comparable effects. Several studies have demonstrated the beneficial effects of this occurrence known as “remote preconditioning” among percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) patients.[3],[4],[5] Moreover, several agents and drugs that somehow activate the pathways involved in preconditioning have been studied to reduce the extent of injury produced in ischemic events.[6],[7],[8]

Preinfarction angina has been recognized as a surrogate for preconditioning ischemic episodes. Lower mortality rates and decreased infarct size have been demonstrated in patients with preinfarction angina in several studies in the thrombolytic era.[9],[10] However, the result of studies on preinfarction angina in patients undergoing primary PCI and its possible cardioprotective effects have been less understood.

This was a single-center prospective cohort study on acute segment elevation myocardial infarction (STEMI) patients undergoing primary PCI. Five hundred and twenty patients were initially evaluated between April 2014 and April 2015. Patients were considered eligible if they were older than 18 years of age, with acute STEMI and indication for primary PCI based on clinical and echocardiographic characteristics. Exclusion criteria were late comers (>24 h from the onset of chest pain); cardiogenic shock at the time of presentation; coronary anatomy or mechanical complications of acute MI requiring emergent surgery; failed thrombolysis; and post-CABG patients. The Institutional Ethics Committee of Rajaie Cardiovascular Medical and Research Center approved the trial design.

Procedural protocol and follow-up

Clinical, laboratory, and procedural characteristics of the studied patients were collected and entered in the questionnaire. Any previous angina's pattern and timing was evaluated by direct interview from the patients. The mentioned interviews were performed by an attending physician not aware of the study protocol. The patients were then divided into three groups based on their previous symptoms:

Asymptomatic: those who had not experienced any previous anginal episodes

Chronic stable angina: those with a stable pattern of anginal episodes not aggravated during the last 4 weeks before the acute MI

Unstable angina: those with new-onset, low-threshold, aggravating or resting angina during the 4 weeks before acute MI.

The patients in each group were also divided into four subgroups regarding the time from symptoms onset: 0–2 h, 2–6 h, 6–12 h or more than 12 h.

The patients received 325 mg aspirin and 600 mg clopidogrel in the emergency department. Coronary angiography and primary PCI procedures were performed according to standard routines. Heparin was administered with the dose of 50–100 IU/kg to maintain an activated clotting time >250–300 s depending on the use of concomitant glycoprotein IIb/IIIa inhibitor. Manual thrombectomy was used in cases with large thrombus burden. Peak cardiac troponin I and creatine-kinase-muscle/brain (CK-MB) levels were defined as the highest amount obtained by serial (three times) enzyme check during the first 24 h of admission. A complete echocardiographic study was performed on the patients the day after the primary PCI. Left ventricular ejection fraction was estimated using the Simpsons equation in the 4 chamber view. All the echocardiograms were performed by one attending physician to avoid inter-observer variability.

The patients were observed during the hospitalization and 6 months period.

Primary and secondary endpoints

The primary endpoints of this study were pre and postprocedural epicardial blood flow of the culprit artery measured as thrombolysis in myocardial infarction (TIMI) flow, and the secondary endpoints were in-hospital mortality and 6 months major adverse cardiac events (defined as death, acute coronary event, target vessel revascularization, and cerebrovascular events).

Statistical analysis

Data were described as mean ± standard deviation for the interval and count (%) for the categorical variables. The fitness of interval data to a normal distribution was assessed by one sample Kolmogorov–Smirnov test. Comparison between the study groups was perfumed by one-way analysis of variance (followed by Bonferroni post hoc test) for the scale, Mann–Whitney U-test for the ordinal and Pearson Chi-square of Fishers exact test for nominal variables. P < 0.05 was considered as statistically significant result. IBM SPSS Statistics® 20 for Windows (IBM Inc., Armonk, NY) was applied for the statistical analysis.

Results

A total of 393 patients were enrolled in the study. Mean age of participants was 58 ± 11 and 317 (80.66%) of the patients were male. The most common cardiovascular risk factor was hypertension observed in 160 (40.7%) patients, followed by dyslipidemia seen in 149 patients (37.9%). 148 (37.7%) of the patients were smokers, 114 (29%) had diabetes mellitus, and 63 (16%) had a positive family history of cardiovascular diseases.

The patients were then divided into three groups regarding previous symptoms: 185 (47.1%) were described as asymptomatic (Group A), 48 (12.2%) had stable angina (Group B) and 160 (40.7%) were categorized as having recent unstable angina (Group C).

There was no statistically significant difference among the three study groups regarding age and cardiovascular risk factors [Table 1].

Table 1: Comparison of the patients' baseline characteristics according to their previous symptoms

Type A coronary lesion was observed in 3 (1.6%) patients in Group A and 6 (3.8%) patients in Group C. Type B lesion was seen in 59 (31.9%),19 (39.6%) and 54 (33.8%) patients in Groups A, B, and C, respectively. 123 (66.5%) patients in Group A, 29 (60.4%) patients in Group B and 100 (62.5%) patients in Group C had Type C coronary lesions.

Bare metal stent was used in 112 (61.9%), 32 (68.1%), and 96 (60%) in Groups A, B, and C, respectively (P = 0.60). Drug-eluting stent was deployed in the remainder of the patients. The distribution of lesion types was identical among study groups (P = 0.28).

There was no significant difference between the three groups regarding pre and post-procedural TIMI flow grades; the respective data are shown in [Table 3] (P = 0.81).

Median of peak post-PCI troponin levels of the three groups were 12.01 (2.77–29), 8.40 (2.89–27.17) and 8.15 (2.30–18.91) in Groups A, B, and C, respectively, which was not significantly different (P = 0.13).

Median of peak post-PCI CK-MB levels of the three groups were 250.5 (115.50–389.00), 200.00 (67.00–369.50), and 176.00 (60.00–313.50). The peak post-PCI CK-MB level was different among groups (P = 0.01), and it was significantly higher in Group A than Group C (P = 0.03).

ST-resolution was seen in 130 (81.25%) of Group A patients, 32 (66.66%) of Group B patients and 116 (62.75%) of Group C patients which was not significantly different (P = 0.78).

Q wave formation was observed in 142 (88.75%), 31 (64.5%) and 96 (52.0%) of Group A, B, and C population, respectively, which was significantly higher in Group A (P = 0.002).

Mitral regurgitation severity was not significantly different among the three groups.

The prevalence of post-PCI complications is summarized in [Table 4]. An intra-aortic balloon pump was inserted for 6 (3.75%), 3 (6.25%), and 8 (4.32%) patients in the Groups A, B and C, respectively.

Data regarding 6 months follow-up of the patients is shown in [Table 5]. There was no significant difference among the three study groups in any of the mentioned outcomes.

Of note, a subgroup analysis of our main study groups was performed based on “time from symptom onset” (0–2 h, 2–6 h, 6 h or more), which the results were not significantly different from the results achieved from the main study groups.

Discussion

This study was designed to evaluate the impact of preinfarction angina on primary PCI patients' outcomes. The patients were divided into three groups with chronic anginal episodes, acute preinfarction episodes and asymptomatic to assess the time-window in which the maximal cardioprotective effects occur. We also analyzed the study variables separately among patients with different ischemic times to detect potential differences associated with different ischemic times. Parameters regarding infarct size, coronary flow, and clinical events were evaluated.

In our study, Q wave formation and peak CKMB levels were significantly higher in patients with unstable angina (defined as patients with angina within 4 weeks before myocardial infarction). Considering q wave and CK levels as surrogates for infarct size,[11],[12] our results suggest that preinfarction angina may have an effect on reducing infarct size. The asymptomatic group had a higher mortality rate in 6 months follow-up than the other two groups which was not statistically significant. None of the evaluated parameters showed significance in multivariate analysis.

The term preconditioning was first introduced in 1986 by Murry et al.[13] as a mechanism in which brief ischemic episodes protected the heart toward consequent major ischemic events. Since then several mechanisms have been discovered regarding this phenomenon such as upregulation of nitric oxide synthase, cyclooxygenase-2, and opening of K ATP channels.[1] Preinfarction angina which is provoked by ischemic episodes before the infarction is thought to trigger preconditioning effects on the heart and is used as a surrogate for them.

Preinfarction angina has been studied widely in AMI patients receiving thrombolytics, and it has been shown to reduce infarct size and mortality.[9],[10]

The effect of preinfarction angina in the setting of primary PCI has been more controversial. There have been mixed results regarding effects on infarct size, mortality and clinical outcomes.

Tomoda and Aoki[14] compared the effects of preinfarction angina among patients treated with fibrinolytics versus PCI. They concluded that patients in the fibrinolytic group with prodromal angina (within 24 h before MI) had lower pump failure, lower CK levels, and higher left ventricular ejection fraction; but in the PCI group, no difference was seen among patients with or without preinfarction angina.

Kluz et al.[16] reported no difference among primary PCI patients with or without preinfarction (7 days prior to MI) angina regarding left ventricular function, heart failure severity index and coronary events in 37 months follow-up. NT pro BNP level was the only biomarker significantly higher in patients with preinfarction angina.

Contrary to mentioned studies, there have been other trials which suggest that there is still a protective role for prodromal angina.

In a retrospective study Luz et al.,[17] evaluated the effect of preinfarction angina defined as anginal pain within the week before the myocardial infarction, among 575 primary PCI patients. Preinfarction angina was an independent protector against moderate-to-severe systolic dysfunction. Only patients with ischemic time of 3–6 h had smaller infarct size (calculated by peak troponin T). Preinfarction angina had no effect on mortality. Contrary to this trial in our study, there was no difference between the results of the whole study population versus the subgroup of patients with 2–6 h from symptoms onset in the evaluated parameters.

In a large prospective study of 16439 primary PCI patients Herrett et al.[18] showed that patients with ischemic symptoms 90 days before AMI have lower 7 days mortality. Lowest mortality was seen in the patients with symptoms nearest to AMI. They also concluded that the early reduction in mortality was followed by an increased late mortality rate. Similar beneficial effects on long-term mortality rates have been reported by Taniguchi et al. in a retrospective study of 5420 primary PCI patients.[19]

Reiter et al.[20] evaluated 1031 primary PCI patients in a retrospective trial. They demonstrated that infarct size was reduced significantly among patients with angina 24 h before acute MI measured by peak CK, CK area under the curve and angiographic area at risk which are in concordance with our study's results. Our results are somehow similar to Reiter's result; however, the timing of preinfarction angina was different in the two studies: 24 h versus 4 weeks.

The indefinite outcomes of studies concerning prodromal angina in primary PCI era may suggest an attenuated protecting role for preconditioning among these patients. This can be due to the complete and timely restoration of perfusion which overshadows the beneficial effects of preconditioning phenomenon. Another issue which has been studied in some trials is the blunting effect of cardiac risk factors such as diabetes mellitus on the effectiveness of the preconditioning process.[21] Furthermore, the reduced rate of mortality and major adverse cardiac events in the setting of primary PCI make the statistical comparison harder and larger populations may be needed to detect potential effects among the study groups.

This was a single-center study with an observational nature. Larger study population and measurement of infarct size with direct imaging modalities could produce more accurate results.

Conclusion

Pre-infarction angina among AMI patients undergoing primary PCI seems to have a limited favorable effect on infarct size; However our study did not show any clinical benefits in primary PCI patients with history of pre-infarction angina.